The long-term objective of this proposal is to develop a better understanding of how the stress forces of blood flow determine the deposition of cholesterol carrying blood proteins in the lining layers of arteries so as to cause human arteriosclerotic diseases such as heart attacks, angina, heart failure, strokes, and gangrene of the extremities. The specific aims of this proposal are to use a newly developed in vitro arterial organ support system (OSS) in which it is possible to maintain an excised animal or human artery in a physiological environment under highly controlled experimental conditions. This degree of experimental control will allow precise measurements of changes in arterial permeability to blood-borne macromolecules, such a radioactively labeled albumin, LDL, and other cholesterol-carrying molecules, that are produced by experimentally-imposed blood pressures and blood flow shear stresses. This new technology will be used in the present proposal to study these permeability vs blood shear stress relationships in the excised Sinclair Research Farm (SRF) minipig thoracoabdominal aorta. The SRF minipig is a widely accepted animal model for studying humanoid atherosclerosis. This tissue model will be used in the OSS to measure the effects on endothelial permeability to 125I-albumin and 125I-LDL that are associated with a varying duration of exposure to different magnitudes and directions of shear stresses. These shear stresses will be created by experimentally imposed flows of normal blood serum and serum containing known or suspected atherogenic risk factors such as hyperlipemia. Data from these studies will provide a number of missing pieces in the atherogenesis-hemodynamic shear stress puzzle. This information will be essential in the design of drugs to block the increased arterial permeability due to these atherogenic hemodynamic shear stress patterns.